NIEHS has a research mandate to understand the role of the environment on the fetal basis of adult disease. We believe that there are a number of facts, in addition to our preliminary data (3);that make a study of the developmental immunotoxicity of atrazine compelling. One, atrazine is both the most heavily used single herbicide employed in USA agriculture at this time and, the most common herbicide contaminant detected in ground water in the USA (http://water.usgs.gov/nawqa). Thus, there is ample risk that the children will be exposed during gestational development or neonatally via the mother's ingestation or bathing in atrazine-contaminated water during pregnancy. Two, there are few published developmental immunotoxicological studies using atrazine. Three, atrazine has been previously shown to affect prenatal development in humans (5, 6). Finally, this research could open the way for mothers'to ameliorate the damage to their fetus by changing water sources, for example. This would also set the stage for others to address intervention effectiveness research in occupational health. Few studies have been performed on the effect of atrazine on the developing immune system. Our preliminary data demonstrated a significant increase in the B cell response, mixed lymphocyte response and cytotoxic T-lymphocyte response of 3 month old male Balb/C mice that were exposed prenatally/lactationally (P/L) to atrazine in an experimental paradigm where the dam received environmentally relevant doses of atrazine via a time-release pellet. The increases in immune function in P/L atrazine males may put them at higher risk to developing autoimmune diseases, e.g., systemic lupus erythematosus, similar to that seen in females. Based on our preliminary P/L atrazine exposure studies, we hypothesize that exposure of Balb/C mice to atrazine during the prenatal, neonatal or a combination period of development induces long term functional changes in their T-cells. We plan to address this hypothesis via the following specific aims. Specific Aim 1: Establish the longitudinal effects of P/L atrazine exposure on the immune system of the offspring. The hypothesis for this specific aim is that P/L atrazine exposure causes precocious immune senescence. Specific Aim 2: Identify the mechanism of the altered immune function at 3 and 6 moa caused by P/L atrazine exposure. PUBLIC HEALTH RELEVANCE 1Atrazine is one of the most heavily used herbicides in the United States of America (USA) with approximately 80 million pounds applied to crops during a growing season. Atrazine and its metabolites are the most common water contaminant in the USA. There have been numerous adult studies done to determine any overt toxic effects of this compound. However, there have been very few studies that study the effects of this compound on the developing fetus even though it is well recognized that fetuses and neonates are exquisitely sensitive to toxic compounds and often have a different array of symptoms that exposed adults. Our preliminary data indicates that the effect of prenatal and lactational exposure to atrazine causes both sex and age-dependent effects on the immune system. Our long range goal is to understand the mechanism of these effects and determine if these animals continue to show a deterioration of their immune response over a 1 year period;a phenomenon that we have termed `precocious immune senescence'.